Attenuated viruses or those that have reduced replication potential have been widely used for a number of therapeutic applications, for example, as vaccines or vaccine vectors, or as gene therapy vectors. Production of attenuated viruses has typically involved the isolation of chance mutations by repeated passage of wild-type virus through unnatural hosts. Advances in recombinant DNA technology and genetic engineering techniques have provided the tools to better develop viruses as therapeutic and prophylactic agents. Recombinant techniques permit the introduction of specific mutations into a selected region of the viral genome and also minimise the reversion of the mutant virus to wild-type.
The ability of many viruses to stimulate both humoral and cell-mediated immunity makes them ideal vaccine vectors and a number of viruses, therefore, have been developed as vaccine vectors for a wide range of diseases including HIV, HCV and cancer. Viruses are also well suited for use as gene therapy vectors. Gene therapy, i.e. the modification of gene expression by the transient or permanent transfer of functional genes to somatic cells, is being intensively developed as a novel approach for preventing and treating disease. Although a variety of physical and chemical methods are known for introducing exogenous nucleic acids into eukaryotic cells, viruses have generally been proven to be much more efficient for this purpose. Several viruses such as parvoviruses, adenoviruses, herpesviruses, retroviruses, rhabdoviruses and poxviruses, have been explored as possible gene therapy vectors (see, for example, U.S. Pat. Nos. 6,440,422; 6,531,123 and 6,451,323).
The engineering of a number of viruses to produce recombinant viruses with specific properties has been described. For example, U.S. Pat. No. 6,497,873 describes a recombinant Rhabdovirus that expresses the F protein of the Paramyxovirus SV5 strain. In this recombinant virus, the F protein is expressed as a fusion protein with a portion of the Rhabdovirus G protein. U.S. Pat. Nos. 6,022,726 and 6,468,544 describe engineered attenuated viruses that include a mutation in a non-coding or coding sequence of a viral nonstructural (NS) gene. Chimeric attenuated viruses which express altered or chimeric viral proteins are also described. U.S. Pat. No. 6,468,544 further describes a live attenuated influenza virus which can induce interferon production in an infected cell.
Engineered viruses have also been described as oncolytic agents, which exploit genetic defects unique to neoplastic cells to replicate in and lyse neoplastic cells, but not non-neoplastic cells. For example, International Patent Applications WO 97/26904 and WO 96/03997 disclose a mutant herpes simplex virus (HSV-1716) that inhibits tumour cell growth, U.S. Pat. No. 6,296,845 describes a mutated adenovirus that is believed to replicate preferentially in p53 negative tumour cells, U.S. Pat. No. 6,110,461 teaches use of a Reovirus for treatment of Ras-mediated neoplasm, and U.S. Pat. No. 6,531,456 describes a recombinant adeno-associated virus vector carrying a drug susceptibility gene and a second gene capable of producing an ancillary effect (such as an interferon or tumour suppressor gene) for use in the treatment of cancer.
As an alternative to genetically engineering viruses, non-pathogenic viruses may be employed, for example, WO 01/19380 describes the use of a Rhabdovirus, and in particular vesicular stomatitis virus (VSV), as a selective oncolytic agent against tumour cells characterized by having low levels of, or no, PKR (double stranded RNA dependent kinase) activity. WO 01/19380 also describes the identification of four mutant VSVs that were susceptible to interferon and their use as oncolytic agents.
This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.